BACKGROUND:Narcolepsy type 1 is characterized by excessive daytime sleepiness, cataplexy, disrupted sleep, sleep paralysis, and hypnagogic or hypnopompic hallucinations. Oveporexton (TAK-861), an oral orexin receptor 2-selective agonist, reduced symptoms of narcolepsy type 1 in a previous phase 2 trial. METHODS:We conducted two phase 3, randomized, placebo-controlled trials evaluating the efficacy and safety of oveporexton over a period of 12 weeks. Participants 16 to 70 years of age with narcolepsy type 1 were randomly assigned in a 3:3:2 ratio to receive twice-daily oveporexton (1 mg or 2 mg) or placebo in the First Light trial and in a 2:1 ratio to receive twice-daily oveporexton (2 mg) or placebo in the Radiant Light trial. The primary end point was the change from baseline to week 12 in mean sleep latency (the ability to stay awake under soporific conditions) on the Maintenance of Wakefulness Test (MWT; range, 0 to 40 minutes; normal, ≥20). Key secondary end points included the change from baseline to week 12 in the Epworth Sleepiness Scale (ESS) total score (range, 0 to 24; normal, <10) and the weekly cataplexy rate at week 12. RESULTS:A total of 168 participants were enrolled in the First Light trial and 105 in the Radiant Light trial. Mean changes from baseline to week 12 in mean sleep latency on the MWT ranged from 14.3 to 19.8 minutes with oveporexton, as compared with -0.4 to -0.8 minutes with placebo (adjusted P<0.001 for all comparisons vs. placebo). Mean changes in the ESS total score ranged from -9.7 to -11.8 with oveporexton, as compared with -1.5 to -1.7 with placebo (adjusted P<0.001 for all comparisons vs. placebo). Median percent reductions in the weekly cataplexy rate ranged from 79.0 to 88.8% with oveporexton, as compared with 27.7 to 39.1% with placebo (adjusted P<0.001 for all comparisons vs. placebo). Adverse events occurred in 86 to 89% of the participants with oveporexton, as compared with 43 to 54% with placebo; the most common adverse events were increased urinary frequency and transient insomnia, which occurred in a majority of participants receiving oveporexton. CONCLUSIONS:Over a period of 12 weeks, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy in participants with narcolepsy type 1. Increased urinary frequency and transient insomnia were common side effects. (Funded by Takeda Development Center Americas; the First Light and Radiant Light ClinicalTrials.gov numbers, NCT06470828 and NCT06505031.).
Objectif La NT1 est une maladie neurologique rare en lien avec la perte des neurones synthétisant l’orexine/hypocrétine. Elle est caractérisée par une somnolence diurne excessive, des cataplexies, des perturbations du sommeil nocturne et des symptômes cognitifs. Oveporexton, un agoniste oral hautement sélectif du récepteur 2 de l’orexine restaure la signalisation de l’orexine. Deux études de phase 3 FirstLight et RadiantLight évaluent l’efficacité, la tolérance et l’impact de oveporexton chez les patients avec NT1. Méthodes Les deux études, randomisées, en double aveugle, versus placebo ont recruté des adultes de 16–70 ans diagnostiqués avec NT1 selon les critères ICSD3/ICSD3-TR, étayés par polysomnographie, ou tests de latence d’endormissement diurne ou concentration d’orexine dans le LCR≤110pg/mL, avec un score ESS ≥11 et ≥4 épisodes de cataplexies hebdomadaires en l’absence de traitement. Ils ont reçu oveporexton (1mg (seulement dans la 3001) ou 2mg, deux fois par jour, oral) ou un placebo, pendant 12 semaines. Les principaux critères d’évaluation étaient l’évolution de la latence du sommeil lors du test de maintien de l’éveil (TME), la réduction de la somnolence (Echelle de somnolence d’Epworth, ESS), la fréquence hebdomadaire des cataplexies (Taux hebdomadaire moyens de cataplexie, WCR) et la survenue d’événements indésirables liés au traitement (EILTs). Résultats Dans les deux essais multicentriques et multinationaux, oveporexton démontre des améliorations statistiquement et cliniquement significatives des symptômes de la narcolepsie de type 1 (Fig. 1). Dans les deux essais, les EILTs étaient principalement de la pollakiurie et des insomnies, aucun EILT grave n’a été observé. 258 (94,5 %) des participants ont terminé les études, parmi lesquels 250 (97 %) ont poursuivi dans l’étude d’extension. Conclusion Dans ces deux études de phase III, oveporexton, administré sur 12 semaines a démontré une efficacité significative sur la vigilance, la somnolence et la fréquence des cataplexies chez les personnes atteintes de NT1, avec une tolérance globale satisfaisante, ouvrant la voie à une nouvelle ère de prise en charge.
Abstract Introduction Narcolepsy type 1 (NT1) is caused by a loss of orexin producing neurons in the hypothalamus. We report a pooled analysis of two randomized, double-blind, phase 3 studies (The First Light: NCT06470828; The Radiant Light: NCT06505031) that evaluated efficacy and safety of oveporexton (TAK-861), an oral orexin receptor 2-selective agonist. Methods Participants were 16–70 years with an International Classification of Sleep Disorders, Third Edition (ICSD-3) or ICSD-3-text revision diagnosis of NT1 supported by sleep tests or orexin cerebrospinal fluid concentrations ≤110 pg/mL; Epworth Sleepiness Scale (ESS) score ≥11; ≥4 partial/complete episodes of cataplexy/week. Participants were randomized to oveporexton 1mg (The First Light only), 2mg, or placebo, twice daily (3 hours apart) for 12 weeks, then either entered a long-term extension study or 4 weeks of follow-up. Primary endpoint: change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT) at week 12. Secondary endpoints: change from baseline in ESS score at week 12, weekly cataplexy rate (WCR) at week 12, and treatment-emergent adverse events (TEAE). Results Overall, 273 participants (54.2% female) were randomized to oveporexton 1mg/1mg (n=61), 2mg/2mg (n=136), or placebo (n=76). Mean baseline age was 31.1 years, ESS score was 18.1, MWT mean sleep latency was 4.8 minutes and median baseline WCR was 26.0 attacks. At week 12, the least square mean differences from placebo (95% CI) for change from baseline in MWT mean sleep latency were 15.90 (12.65, 19.15) minutes (1mg/1mg oveporexton) and 19.16 (16.65, 21.68) minutes (2mg/2mg; both nominal P< 0.001), and in ESS total score −8.27 (−9.82, −6.73; 1mg/1mg) and −9.71 (−10.92, −8.50; 2mg/2mg; both nominal P< 0.001). Oveporexton decreased WCR at week 12 (incidence rate ratio [95% CI] vs placebo: 1mg/1mg, 0.28 [0.19,0.41], 2mg/2mg, 0.32 [0.23,0.45]; both nominal P< 0.001). The most common TEAEs with oveporexton were pollakiuria and insomnia; 6 participants (1mg/1mg oveporexton n=3; 2mg/2mg n=2; placebo n=1) had TEAEs leading to study drug discontinuation. 258 participants completed study treatment and 250 continued into the long-term extension. Conclusion In this pooled analysis, oveporexton treatment improved measures of wakefulness, sleepiness, and cataplexy frequency and was generally well tolerated. Support (if any) Funding by Takeda Development Center Americas, Inc.
